Viral-specific cytotoxic T-cell responses in HLA-sensitized kidney transplant patients maintained on everolimus and low-dose tacrolimus.

BACKGROUND: Maintenance with "everolimus + reduced dose tacrolimus" (Ev + Taclow ) was reported to reduce the risk of viral infections compared to "tacrolimus + mycophenolate mofetil" (Tac + MMF). Here we examined viremia and viral-specific T-cell (viral-Tc) responses in patients treated with Ev + Taclow versus Tac + MMF in highly-human leukocyte antigen (HLA)-sensitized patients. METHODS: HLA-sensitized (HS) kidney transplant patients were monitored pre- and post-transplant for viremia (cytomegalovirus (CMV), BK, and Epstein-Barr virus (EBV)) by polymerase chain reaction (PCR) in 19 Ev + Taclow and 48 Tac + MMF patients. For CMV PCR analysis, we compared infection rates in 19 Ev + Taclow patients to 48 CMV D+/R- (#28) or CMV D-/R- (#20) Tac + MMF patients. CMV-specific cytotoxic T cell (CMV-Tc) and EBV-specific cytotoxic T cell (EBV-Tc) were evaluated by cytokine flow cytometry, and donor-specific antibody (DSA) levels by Luminex for selected patients in both groups. RESULTS: CMV and EBV viremia rates were similar in Ev + Taclow versus Tac + MMF patients, but BK virus (BKV) rates were significantly higher in Ev + Taclow patients. No patient in either group developed BK virus-associated allograft nephropathy (BKAN) or post-transplant lymphoproliferative disorders (PTLD). CMV-Tc and EBV-Tc decreased significantly after alemtuzumab induction but returned to pre-treatment levels 1-2 months post-transplant in most patients. de novo DSA was similar in both groups as were patient and graft survival and graft rejection. CONCLUSIONS: CMV-Tc and EBV-Tc were similar in Ev + Taclow and Tac + MMF patients. EBV and CMV viremia rates were similar over 1 year. BKV rates were significantly higher in Ev + Taclow patients suggesting no benefit for Ev + Taclow in enhancing viral-Tc effector functions or limiting viral infections.

Cytomegalovirus Immunity After Alemtuzumab Induction in Desensitized Kidney Transplant Patients.

BACKGROUND: Desensitization with IVIG + rituximab combined with alemtuzumab induction gives HLA-sensitized patients an opportunity for successful kidney transplantation. However, it may be associated with a high risk for viral infections due to combined T cell and B cell depletion. METHODS: Anti-cytomegalovirus (CMV) activity was assessed in 280 pretransplant and posttransplant blood samples from 33 desensitized patients who received alemtuzumab induction. CMV-specific CD8+ (CMV-Tc), CD4+ (CMV-Th) T cell activity, and natural killer (NK) cell number were measured by flow cytometry. Anti-CMV IgG was measured by enzyme-linked immunosorbent assay, and CMV DNA by polymerase chain reaction. RESULTS: All 30 CMV sero (+) patients were (+) for CMV-Tc and/or Th predesensitization, while 3 sero (-) patients showed no CMV-T cell activity. CMV-Tc and/or Th became (-) in 50% to 70% of these sero (+) patients at 1 month post-alemtuzumab. However, 75% showed CMV-T cell (+) by 2 months and 95% did so by 3 months post-alemtuzumab. More than 50% of pretranslpant NK cell levels were detected post-alemtuzumab. Anti-CMV IgG levels did not decrease posttransplant in sero (+) patients. Four patients developed CMV viremia with clearance by 1.2 months, which correlated with an increase or appearance of CMV-T cells, even in the sero (-) patient. CONCLUSIONS: CMV-T cell activity, anti-CMV IgG, and NK cell-mediated antibody-dependent cell cytotoxicity were present in aleumtuzumab-treated CMV sero (+) patients. One sero (-) patient developed CMV-T cell responses post-CMV viremia. These results suggest that the IVIG + rituximab desensitization combined with alemtuzmab induction with triple immunosuppression maintenance does not result in prolonged suppression of anti-CMV immunity or increased risk for CMV infection.